Fundamental Evaluation Regarding the Relationship Between Albumin-binding and Tumor Accumulation of PSMA-targeting Radioligands

Overview

Journal Ann Nucl Med

Date 2024 Apr 27

PMID 38676906

Authors

Nobuki Kazuta

Shohei Tsuchihashi

Hiroyuki Watanabe

Masahiro Ono

Affiliations

Soon will be listed here.

Abstract

Objective: The marked success of prostate-specific membrane antigen (PSMA)-targeting radioligands with albumin binder (ALB) is attributed to the improvement of blood retention and tumor accumulation. [In]In-PNT-DA1, our PSMA-targeting radioligand with ALB, also achieved improved tumor accumulation due to its prolonged blood retention. Although the advantage of ALBs is related to their reversible binding to albumin, the relationship between albumin-binding and tumor accumulation of PSMA-targeting radioligands remains unclear because of the lack of information about radioligands with stronger albumin-binding than ALBs. In this study, we designed and synthesized [In]In-PNT-DM-HSA, a new radioligand that consists of a PSMA-targeting radioligand covalently bound to albumin. The pharmacokinetics of [In]In-PNT-DM-HSA was compared with those of [In]In-PNT-DA1 and [In]In-PSMA-617, a non-ALB-conjugated radioligand, to evaluate the relationship between albumin-binding and tumor accumulation.

Method: The [In]In-PNT-DM-HSA was prepared by incubation of [In]In-PNT-DM, a PSMA-targeting radioligand including a maleimide group, and human serum albumin (HSA). The ability of [In]In-PNT-DM-HSA was evaluated by in vitro assays. A biodistribution study using LNCaP tumor-bearing mice was conducted to compare the pharmacokinetics of [In]In-PNT-DM-HSA, [In]In-PNT-DA1, and [In]In-PSMA-617.

Results: The [In]In-PNT-DM-HSA was obtained at a favorable radiochemical yield and high radiochemical purity. In vitro assays revealed that [In]In-PNT-DM-HSA had fundamental characteristics as a PSMA-targeting radioligand interacting with albumin covalently. In a biodistribution study, [In]In-PNT-DM-HSA and [In]In-PNT-DA1 showed higher blood retention than [In]In-PSMA-617. On the other hand, the tumor accumulation of [In]In-PNT-DA1 was much higher than [In]In-PNT-DM-HSA and [In]In-PSMA-617.

Conclusions: These results indicate that the moderate reversible binding of ALB with albumin, not covalent binding, may play a critical role in enhancing the tumor accumulation of PSMA-targeting radioligands.

Citing Articles

Effect of Linker Entities on Pharmacokinetics of In-Labeled Prostate-Specific Membrane Antigen-Targeting Ligands with an Albumin Binder.

Kazuta N, Nakashima K, Watanabe H, Ono M ACS Pharmacol Transl Sci. 2024; 7(8):2401-2413.

PMID: 39144550 PMC: 11320743. DOI: 10.1021/acsptsci.4c00257.

References

He M, Cao Y, Chi C, Zhao J, Chong E, Chin K . Unleashing novel horizons in advanced prostate cancer treatment: investigating the potential of prostate specific membrane antigen-targeted nanomedicine-based combination therapy. Front Immunol. 2023; 14:1265751. PMC: 10545965. DOI: 10.3389/fimmu.2023.1265751. View

An S, Huang G, Liu J, Wei W . PSMA-targeted theranostics of solid tumors: applications beyond prostate cancers. Eur J Nucl Med Mol Imaging. 2022; 49(12):3973-3976. DOI: 10.1007/s00259-022-05905-7. View

He M, Cao Y, Chi C, Yang X, Ramin R, Wang S . Research progress on deep learning in magnetic resonance imaging-based diagnosis and treatment of prostate cancer: a review on the current status and perspectives. Front Oncol. 2023; 13:1189370. PMC: 10400334. DOI: 10.3389/fonc.2023.1189370. View

Jeitner T, Babich J, Kelly J . Advances in PSMA theranostics. Transl Oncol. 2022; 22:101450. PMC: 9123266. DOI: 10.1016/j.tranon.2022.101450. View

Lau J, Jacobson O, Niu G, Lin K, Benard F, Chen X . Bench to Bedside: Albumin Binders for Improved Cancer Radioligand Therapies. Bioconjug Chem. 2019; 30(3):487-502. DOI: 10.1021/acs.bioconjchem.8b00919. View

Unterrainer L, Calais J, Bander N . Prostate-Specific Membrane Antigen: Gateway to Management of Advanced Prostate Cancer. Annu Rev Med. 2024; 75:49-66. DOI: 10.1146/annurev-med-081522-031439. View

Aboagye E, Barwick T, Haberkorn U . Radiotheranostics in oncology: Making precision medicine possible. CA Cancer J Clin. 2023; 73(3):255-274. DOI: 10.3322/caac.21768. View

Tsuchihashi S, Nakashima K, Tarumizu Y, Ichikawa H, Jinda H, Watanabe H . Development of Novel In/Ac-Labeled Agent Targeting PSMA for Highly Efficient Cancer Radiotheranostics. J Med Chem. 2023; 66(12):8043-8053. DOI: 10.1021/acs.jmedchem.3c00346. View

Dumelin C, Trussel S, Buller F, Trachsel E, Bootz F, Zhang Y . A portable albumin binder from a DNA-encoded chemical library. Angew Chem Int Ed Engl. 2008; 47(17):3196-201. DOI: 10.1002/anie.200704936. View

10.

Brandt M, Cardinale J, Giammei C, Guarrochena X, Happl B, Jouini N . Mini-review: Targeted radiopharmaceuticals incorporating reversible, low molecular weight albumin binders. Nucl Med Biol. 2019; 70:46-52. DOI: 10.1016/j.nucmedbio.2019.01.006. View

11.

Hu H, Quintana J, Weissleder R, Parangi S, Miller M . Deciphering albumin-directed drug delivery by imaging. Adv Drug Deliv Rev. 2022; 185:114237. PMC: 9117484. DOI: 10.1016/j.addr.2022.114237. View

12.

Yi C, Xie F, Xu X, Xiao D, Zhou X, Cheng M . Guanidine-modified albumin-MMAE conjugates with enhanced endocytosis ability. Drug Deliv. 2023; 30(1):2219433. PMC: 10339779. DOI: 10.1080/10717544.2023.2219433. View

13.

Sugio S, Kashima A, Mochizuki S, Noda M, Kobayashi K . Crystal structure of human serum albumin at 2.5 A resolution. Protein Eng. 1999; 12(6):439-46. DOI: 10.1093/protein/12.6.439. View

14.

Liu T, Liu C, Ren Y, Guo X, Jiang J, Xie Q . Development of an Albumin-Based PSMA Probe With Prolonged Half-Life. Front Mol Biosci. 2021; 7:585024. PMC: 7773938. DOI: 10.3389/fmolb.2020.585024. View

15.

Eisenwiener K, Powell P, Macke H . A convenient synthesis of novel bifunctional prochelators for coupling to bioactive peptides for radiometal labelling. Bioorg Med Chem Lett. 2000; 10(18):2133-5. DOI: 10.1016/s0960-894x(00)00413-3. View

16.

Feng L, Fang J, Zeng X, Liu H, Zhang J, Huang L . Ga-Labeled Maleimide for Blood Pool and Lymph PET Imaging through Covalent Bonding to Serum Albumin In Vivo. ACS Omega. 2022; 7(32):28597-28604. PMC: 9386703. DOI: 10.1021/acsomega.2c03505. View

17.

Leggio C, Galantini L, Pavel N . About the albumin structure in solution: cigar Expanded form versus heart Normal shape. Phys Chem Chem Phys. 2008; 10(45):6741-50. DOI: 10.1039/b808938h. View

18.

Iikuni S, Ono M, Watanabe H, Shimizu Y, Sano K, Saji H . Cancer radiotheranostics targeting carbonic anhydrase-IX with In- and Y-labeled ureidosulfonamide scaffold for SPECT imaging and radionuclide-based therapy. Theranostics. 2018; 8(11):2992-3006. PMC: 5996370. DOI: 10.7150/thno.20982. View

19.

Iikuni S, Tarumizu Y, Nakashima K, Higaki Y, Ichikawa H, Watanabe H . Radiotheranostics Using a Novel Ac-Labeled Radioligand with Improved Pharmacokinetics Targeting Prostate-Specific Membrane Antigen. J Med Chem. 2021; 64(18):13429-13438. DOI: 10.1021/acs.jmedchem.1c00772. View

20.

Baldwin A, Kiick K . Tunable degradation of maleimide-thiol adducts in reducing environments. Bioconjug Chem. 2011; 22(10):1946-53. PMC: 3220410. DOI: 10.1021/bc200148v. View